Smoking poses a serious threat to global health. In the United States alone, annual mortality from smoking (including environmental exposure, i.e. “second-hand smoke”) surpasses 443,000. Furthermore, smoking significantly increases the risk of various diseases such as coronary artery disease, stroke, lung cancer, and chronic obstructive pulmonary disease. An estimated 46 million people in the United States are smokers, 20.6 percent of the US population.
More than 40 percent of existing smokers attempt to quit smoking annually. Various approved therapies (Chantix™, bupropion, nicotine patch/gum, hypnotherapy, biofeedback) have long been in clinical use to treat nicotine dependence. Existing therapies directed toward smoking cessation tend to focus on counseling, behavioral treatment such as hypnosis, or chemical/pharmaceutical therapies. Overall there are mixed results from current therapeutic options. Each of these agents have only shown moderate efficacy, as evidenced by the present rate of only 10% successful abstinence annually. There seems to be a time period (first 2-4 weeks) where smokers struggle with craving and anxiety. Current literature indicates that both Chantix™ and bupropion have very low (less than 25%) success rates in the first few weeks of treatment intervention.
Given the immense harm of smoking to the human body, the high degree of cost to the health care system, the addictive nature of smoking, and the high level of treatment resistance with respect to conventional therapy, there remains an acute need for effective strategies for smoking cessation.
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. Eight serotypes, A-G (including C1 and C2), are known. Botulinum toxin type A is the most lethal natural biological agent known to man.
Botulinum toxin comprises a two-chain protein composed of a light chain (molecular weight ca. 50 kDa) covalently bound by a single disulfide bond to a heavy chain (molecular weight ca. 100 kDa). Hence, the molecular weight of each two-chain protein for all known botulinum toxins is about 150 kDa. The light chain bears the domain which exhibits intracellular biological (protease) activity, while the heavy chain comprises the receptor binding (immunogenic) and cell membrane translocational domains.
The various serotypes of botulinum toxin occur in nature as complexes comprising the 150 kDa core two-chain protein associated with certain non-toxin proteins. Thus, the botulinum toxin type A complex can be produced by Clostridial bacteria as 300 kDa, 500 kDa and 900 kDa forms. Botulinum toxin types B and C1 are produced as 500 kDa and 700 kDa complexes. Botulinum toxin type D is produced as both 300 kDa and 500 kDa complexes. Botulinum toxin types E and F are produced only as approximately 500 kDa complexes. The botulinum toxin complexes are believed to contain a non-toxin hemagglutinin protein and a non-toxin non-hemagglutinin protein. These two non-toxin proteins are believed to stabilize botulinum toxin against denaturation and to protect botulinum toxin against digestive acids when it is ingested. Additionally, it is possible that the larger (greater than about 150 kDa molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. In 1989 a type A botulinum toxin was first approved by the U.S. Food and Drug Administration (FDA) for clinical use in the treatment of blepharospasm, strabismus and hemifacial spasm. Subsequently, a botulinum toxin type A was also approved by the FDA for the treatment of cervical dystonia and for the treatment of glabellar lines, and a botulinum toxin type B was approved for the treatment of cervical dystonia.
Botulinum toxin also has been proposed for or has been used to treat skin wounds (U.S. Pat. No. 6,447,787), various autonomic nerve dysfunctions (U.S. Pat. No. 5,766,605), tension headache, (U.S. Pat. No. 6,458,365), migraine headache (U.S. Pat. No. 5,714,468), sinus headache (U.S. patent application publication 2004/0219172-A1), post-operative pain and visceral pain (U.S. Pat. No. 6,464,986), neuralgia pain (U.S. patent application publication 2004/0028706-A1), hair growth and hair retention (U.S. Pat. No. 6,299,893), fibromyalgia (U.S. Pat. No. 6,623,742), various skin disorders (U.S. patent application publication 2005/0123567-A1), motion sickness (U.S. patent application publication 2005/0147625-A1), psoriasis and dermatitis (U.S. Pat. No. 5,670,484), injured muscles (U.S. Pat. No. 6,423,319), various cancers (U.S. Pat. No. 6,139,845), smooth muscle disorders (U.S. Pat. No. 5,437,291), down-turned mouth corners (U.S. Pat. No. 6,358,917), nerve entrapment syndromes (U.S. patent application publication 2003/0224019-A1), various impulse disorders (U.S. patent application publication 2004/0213811-A1), acne (WO 03/011333), and neurogenic inflammation (U.S. Pat. No. 6,063,768).
Botulinum toxin A is presently commercially available as Botox™ (Allergan, Inc., Irvine, Calif.), Dysport™ (Ipsen, Berkshire, UK), and Xeomin™ (Merz, Frankfurt, Germany). Another botulinum toxin type A drug, PurTox™ (Mentor, Santa Barbara, Calif.), is currently in the FDA regulatory process. Meditoxin™ (Medy-Tox, Seoul, Korea), also known as Neuronox™ or Siax™, is a type A botulinum toxin available internationally and is in clinical trials in the United States. Another type A botulinum toxin is currently marketed in Brazil as Prosigne™ (Lanzhou Institute of Biological Products, China). The success of botulinum toxin A to treat a variety of clinical conditions has led to interest in other botulinum toxin serotypes. Botulinum toxin type B is commercialized as Neurobloc™/Myobloc™ (Solstice Neuroscience, Inc., San Francisco, Calif.).